REPORT

Mutations in KCTD1 Cause Scalp-Ear-Nipple Syndrome

Alexander G. Marneros,1,18 Anita E. Beck,2,18 Emily H. Turner,3,18 Margaret J. McMillin,2

Matthew J. Edwards,4 Michael Field,5 Nara Lygia de Macena Sobreira,6 Ana Beatriz A. Perez,7

Jose A.R. Fortes,8 Anne K. Lampe,9 Maria Luisa Giovannucci Uzielli,10,11 Christopher T. Gordon,12,13

Ghislaine Plessis,14 Martine Le Merrer,14 Jeanne Amiel,14 Ernst Reichenberger,15 Kathryn M. Shively,2

Felecia Cerrato,16 Brian I. Labow,16 Holly K. Tabor,17 Joshua D. Smith,3 Jay Shendure,3

Deborah A. Nickerson,3 Michael J. Bamshad,2,3,* and the University of Washington Center forMendelian Genomics

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of

the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex

family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause

SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1missensemutations in each family tested.

All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain

that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2a (TFAP2A) via its

BTB domain, andmutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a poten-

tial overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for

this BTB-domain-containing transcriptional repressor during ectodermal development.

Scalp-Ear-Nipple (SEN) syndrome (MIM 181270), or Fin-

lay-Marks syndrome, is a rare autosomal-dominant

disorder first described in 1978 by Finlay and Marks,1

and to date, fewer than 15 independent cases have been re-

ported.2–12 SEN syndrome is characterized by aplasia cutis

congenita (ACC) of the scalp, breast abnormalities that

range from hypothelia or athelia to amastia, and minor

anomalies of the external ears (Figure 1). Less frequent

clinical characteristics include nail dystrophy, dental

anomalies, cutaneous syndactyly of the digits, and renal

malformations. The penetrance of SEN syndrome appears

to be high, although it exhibits substantial variable expres-

sivity within families. The phenotypic features of SEN

syndrome overlap with those of several syndromes,

perhaps most notably ulnar-mammary syndrome (MIM

181450) and ectrodactyly with ectodermal dysplasia and

cleft lip/palate syndrome (MIM 129900). Nevertheless,

despite screening of candidate genes (e.g., TBX3 [MIM

601621] and TP63 [MIM 603273]) in which mutations

cause syndromes with similar phenotypic characteristics

(data not shown), the genetic basis of SEN syndrome

remains unknown.

1Cutaneous Biology Research Center, Massachusetts General Hospital, Charlest

Seattle, WA 98195, USA; 3Department of Genome Sciences, University of Wash

Sydney, Campbelltown, NSW 2560, Australia; 5Genetics of Learning Disabil6McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University,

Department of Morphology and Genetics, Universidade Federal de Sao Paulo,

Universidade Catolica do Parana, Curitiba 1155, Brasil; 9South East of Scotlan

UK; 10Department of Genetics and Molecular Medicine, University of Florence

National de la Sante et de la RechercheMedicale U781, Departement de Geneti

Descartes-Sorbonne Paris Cite, Institut Imagine, Paris 75015, France; 14Service d

Nacre, Caen 14033 Cedex 9, France; 15Department of Reconstructive Science16Department of Plastic and Oral Surgery, Boston Children’s Hospital, Bosto

Children’s Research Institute, Seattle, WA 98101, USA18These authors contributed equally to this work

*Correspondence: mbamshad@uw.edu

http://dx.doi.org/10.1016/j.ajhg.2013.03.002. �2013 by The American Societ

The Am

To identify causative mutations for SEN syndrome, we

performed a genome-wide linkage scan under a dominant

model (f1¼ 1; q¼ 0.0001) by using short tandem repeats in

the ABI PRISM Linkage Mapping Set Version 2.5 MD10 on

a large pedigree with 15 affected individuals spanning four

generations previously reported by Edwards et al. (family A

in Figure 2; Table 1 and Table S1, available online). This

linkage-mapping set used 382 autosomal and 18 X-linked

microsatellite markers to define an approximately 10 cM

resolution human index map. A pairwise maximum LOD

score (Zmax) of 2.94 was obtained with the marker

D18S53 at a recombination fraction (Q) of 0.001 (no other

linkage peaks were found; Table S2). Haplotype analysis

defined a ~42.9 Mb critical interval containing ~206 genes

between D18S452 and D18S474. Without an obvious

candidate gene within this interval to test, we next per-

formed exome sequencing of the two most distantly

related affected individuals in family A (Figure 2) and of

the affected individuals from two additional unrelated

families (families B and C in Figure 2). All studies were

approved by the institutional review boards of the Univer-

sity of Washington and Seattle Children’s Hospital, and

own,MA 02129, USA; 2Department of Pediatrics, University ofWashington,

ington, Seattle, WA 98195, USA; 4School of Medicine, University of Western

ities Service, Hunter Genetics, Waratah, Newcastle, NSW 2298, Australia;

School of Medicine, Baltimore, MD 21205, USA; 7Clinical Genetics Center,

Sao Paulo 04021-001, Brazil; 8Departament of Internal Medicine, Pontifıcia

d Clinical Genetic Service, Western General Hospital, Edinburgh EH4 2XU,

, Florence 50132, Italy; 11Genetic Science, Florence I-50132, Italy; 12Institut

que, Hopital Necker Enfants Malades, Paris 75015, France; 13Universite Paris

e Genetique, Centre Hospitalier Universitaire de Caen, Hopital de la Cote de

s, University of Connecticut Health Center, Farmington, CT 06030, USA;

n, MA 02115, USA; 17Treuman-Katz Center for Pediatric Bioethics, Seattle

y of Human Genetics. All rights reserved.

erican Journal of Human Genetics 92, 621–626, April 4, 2013 621

Figure 1. Characteristic Physical Find-ings in Individuals with SEN SyndromeClinical characteristics of SEN syndromeinclude cutis aplasia of the vertex of thescalp (A, B, and D), minor external eardefects, such as overfolded helix andanteverted ears (C and F), and aplasia ofthe nipples and sparse or absent secondarysexual hair (G and H). Less common find-ings include syndactyly and nail dysplasia(E) and craniofacial malformations suchas telecanthus, a broad, flat nasal bridge,and frontal bossing (F). Case identifiersE:III-1 (A–C), F:II-1 (F), J:I-1 (D and H),and J:II-1 (E and G) correspond to thosein Table 1 and Table S1, where a detaileddescription of the phenotype of eachaffected individual is provided.

informed consent was obtained from participants or their

parents.

In brief, 1 mg of genomic DNAwas subjected to a series of

shotgun library construction steps, including fragmenta-

tion through acoustic sonication (Covaris), end polishing

(NEBNext End Repair Module), A tailing (NEBNext dA-

Tailing Module), and ligation of 8 bp barcoded sequencing

adaptors (Enzymatics Ultrapure T4 Ligase). Prior to exome

capture, the library was amplified via PCR (BioRad iProof).

One microgram of barcoded shotgun library was hybrid-

ized for the capture of probes targeting 64 Mb of coding

exons and miRNA (Roche Nimblegen SeqCap EZ Human

Exome Library v.3.0) per the manufacturer’s protocol,

and custom blockers complimentary to the full length of

the flanking adaptor and barcodes were added. Enriched

libraries were amplified via PCR before sequencing (BioRad

iProof). Library quality was determined by the examina-

tion of molecular-weight distribution and sample concen-

tration (Agilent Bioanalyzer). Pooled, barcoded libraries

were sequenced via paired-end 50 bp reads with an 8 bp

barcode read on Illumina HiSeq sequencers.

Demultiplexed BAM files were aligned to a human refer-

ence (UCSC Genome Browser hg19) with the Burrows-

622 The American Journal of Human Genetics 92, 621–626, April 4, 2013

Wheeler Aligner.13 Read data from

a flow-cell lane were treated indepen-

dently for alignment and quality-

control purposes in instances where

the merging of data from multiple

lanes was required. All aligned

read data were subjected to: (1)

removal of duplicate reads (Picard),

(2) indel realignment with the GATK

IndelRealigner, and (3) base-

quality recalibration with GATK

TableRecalibration. Variant detection

and genotyping were performed with

the UnifiedGenotyper tool from

GATK (refv.1.529). Variant data for

each sample were formatted (in

variant call format [VCF]) as ‘‘raw’’

calls that contained individual genotype data for one or

multiple samples. Low-quality and potentially false-posi-

tive sites (e.g., those with quality scores% 50, allelic imbal-

ance R 0.75, long homopolymer runs [>3], and/or low

quality by depth [<5]) were flagged with the filtration

walker (GATK). Variant data were annotated with the Seat-

tleSeq Annotation Server.

The region under the linkage peak was examined for rare

and/or unique functional variation, including indels and

missense, nonsense, and splice-site mutations, shared

among affected individuals in family A. Variants found in

dbSNP v.134 or in ~1,530 exomes from a subset of the

National Heart, Lung, and Blood Institute (NHLBI) Exome

Sequencing Project (ESP) were excluded prior to analysis

for all sequenced individuals. This approach identified two

genes, KCTD1 (MIM 613420) and EPG5, with candidate

missense variants. In the exome data from the two addi-

tional unrelated affected individuals with SEN syndrome,

nocandidate variantswere identified inEPG5, but each indi-

vidualhadadifferentmissensemutationinKCTD1 (Figure3,

Table 1, andTable S1). The presence of each variant found in

KCTD1 (RefSeq accession number NM_001258221.1) was

subsequently confirmed by Sanger sequencing.

+

+

+

_ _

_ _ _ _+

+

+

++

++

+ +

+

+

I

II

III

IV

V

+ _

+

+

_

_ +

A B

+ + + +

C D E F

G H I J

I

II

III

I

II

1

1 2

2

+

__

_

2

21

1 1

1

1 1 1 1

_

+

_

1

1

2

+

1

Figure 2. Pedigrees of Families A–JPedigrees illustrating the relationships andaffected status of ten families affected bySEN syndrome. Case identifiers correspondto those in Table 1 and Table S1. Grey dotsindicate individuals who underwentexome sequencing. Plus signs (þ) indicateindividuals in whommutations were iden-tified, andminus signs (–) indicate individ-uals in whom no mutation was found.Family A individuals with a plus or minussign (except individuals IV-14 and V-6)were also included in the linkage analysis.

To determine the extent to which KCTD1 mutations

explain cases of SEN syndrome, we used Sanger sequencing

to screen seven additional unrelated families (Figure 2)

with a total of nine affected individuals available for

sequencing. We identified missense mutations in KCTD1

in all seven families (Figure 3, Table 1, and Table S1).

Collectively, between the three families used for discovery

and the seven families used for validation studies, KCTD1

mutations were found in all ten kindreds tested. Accord-

ingly, there is no evidence that SEN syndrome is geneti-

cally heterogeneous.

In total, ten unique missense KCTD1 mutations were

identified in either exon two (n ¼ 7) or exon three

(n ¼ 3) of KCTD1 (Figure 3, Table 1, and Table S1). None

of the KCTD1 missense mutations identified in the

subjects were found in >13,000 chromosomes sequenced

as part of the NHLBI ESP. The clinical characteristics of

individuals with different KCTD1 mutations were similar

to one another (Table 1 and Table S1), despite the variable

expressivity of SEN syndrome within families. Addition-

ally, no heterozygous pathogenic KCTD1 variants were

found in six tested families affected by dominantly in-

herited isolated ACC (MIM 107600).

KCTD1 is a member of a family of proteins that contain

a potassium-channel tetramerization domain (KCTD).14,15

The amino acid sequence of KCTD1 is highly conserved,

and humans and mice differ only by an 8 aa insertion

immediately following the start codon; humans and rats

differ only by a single amino acid residue.14 The

The American Journal of Huma

N-terminal KCTD (T1) of KCTD1

overlaps with a bric-a-brac, tram

track, and broad complex (BTB)

domain (T1-type BTB domain), which

is commonly found in transcriptional

regulators that contain zinc-finger

motifs and that mediate protein-

protein interactions.16 The BTB

domain of KCTD1 has been shown

to mediate the transcriptional

repressor activity of KCTD1 and to

be required for the homomerization

of KCTD1 proteins.14 Thus, alter-

ations within the BTB domain of

KCTD1 would be predicted to affect its transcriptional

repressor activity.

From Drosophila to humans, highly conserved BTB

domains are involved in dimerization, transcriptional

repression, and nuclear localization. Crystollographic

analysis of the BTB domain in human promyelocytic

leukemia zinc finger (PLZF) identified a charged pocket

formed by the apposition of two BTB monomers.17 Proper

alignment of charge within this pocket is essential for BTB

to act as a transcriptional repressor because altering the

charge of critical residues (Asp35 and Arg49 in PLZF) in

the BTB pocket results in partial or complete loss of

repressor activity.

All of the KCTD mutations that cause SEN syndrome are

missense mutations predicted to alter BTB-domain resi-

dues, including several residues that form the BTB pocket

or that are adjacent to such residues. Specifically, in the

crystal structure of the PLZF BTB domain, the floor of the

pocket is formed by residues 33–35 whereas each wall is

formed by residues 63, 64, and 66–68.17 Accordingly, we

predict that KCTD1 mutations that cause SEN syndrome

are likely to affect the transcriptional repressor activity of

the BTB domain. Clustering of missense mutations within

a structural hotspot and the absence of stops, frameshifts,

and splice-site mutations could mean that the missense

mutations we have identified cause loss of function via

a dominant-negative mechanism. This would be consis-

tent with the observation that KCTD1 forms homodimers

and that some alterations of the PLZF pocket reduce

n Genetics 92, 621–626, April 4, 2013 623

Table 1. Mutations and Clinical Findings of Individuals with SEN Syndrome

Case Reference Ancestry Gender

Mutation Information Clinical Findings

KCTD1Exon

NucleotideChange

GERPScore

AminoAcidChange

PredictedEffect

CutisAplasia

EarAnomaly

Absent orHypoplasticNipplesand/orBreast

Family A

II-8 Edwards et al.4 European male 2 c.89C>A 5.68 p.Ala30Glu missense þ þ þ

III-4 Edwards et al.4 European male 2 c.89C>A 5.68 p.Ala30Glu missense þ þ þ

III-7 Edwards et al.4 European female 2 c.89C>A 5.68 p.Ala30Glu missense þ þ þ

III-8 Edwards et al.4 European male NT NT NT NT NT þ þ �

IV-5 Edwards et al.4 European female 2 c.89C>A 5.68 p.Ala30Glu missense þ þ �

IV-6 Edwards et al.4 European female 2 c.89C>A 5.68 p.Ala30Glu missense þ þ �

IV-8 Edwards et al.4 European male 2 c.89C>A 5.68 p.Ala30Glu missense þ þ þ

IV-10 Edwards et al.4 European female 2 c.89C>A 5.68 p.Ala30Glu missense þ þ þ

IV-11 Edwards et al.4 European male 2 c.89C>A 5.68 p.Ala30Glu missense þ þ þ

V-1 Edwards et al.4 European male 2 c.89C>A 5.68 p.Ala30Glu missense þ ND ND

V-3 Edwards et al.4 European female 2 c.89C>A 5.68 p.Ala30Glu missense þ þ þ

V-4 Edwards et al.4 European female NT NT NT NT NT þ þ þ

V-5 Edwards et al.4 European male 2 c.89C>A 5.68 p.Ala30Glu missense þ ND ND

V-6 Edwards et al.4 European female 2 c.89C>A 5.68 p.Ala30Glu missense þ þ þ

Family B

II-2 NA European female 2 c.92C>T 5.68 p.Pro31Leu missense þ þ þ

III-1 NA European male 2 c.92C>T 5.68 p.Pro31Leu missense þ þ þ

III-4 NA European female NT NT NT NT NT þ þ þ

Family C

II-2 NA European female 2 c.58C>T 5.68 p.Pro20Ser missense þ þ þ

III-1 NA European male 2 c.58C>T 5.68 p.Pro20Ser missense þ þ þ

Family D

II-1 Sobreira et al.9 Brazilian male 2 c.99C>A 5.68 p.His33Gln missense þ þ þ

Family E

II-1 NA European female 2 c.98A>C 5.68 p.His33Pro missense þ þ þ

III-1 NA European female 2 c.98A>C 5.68 p.His33Pro missense þ þ �

Family F

II-1 NA European female 3 c.207C>A 5.78 p.Asp69Glu missense þ þ þ

Family G

II-1 Le Merrer et al.12 North African female 2 c.92C>G 5.68 p.Pro31Arg missense þ þ þ

Family H

II-1 Plessis et al.8 European female 3 c.221A>C 5.78 p.His74Pro missense þ þ þ

Family I

I-1 Picard et al.7 European male NT NT NT NT NT þ þ þ

II-1 Picard et al.7 European female 3 c.185G>A 5.63 p.Gly62Asp missense þ � �

(Continued on next page)

624 The American Journal of Human Genetics 92, 621–626, April 4, 2013

Table 1. Continued

Case Reference Ancestry Gender

Mutation Information Clinical Findings

KCTD1Exon

NucleotideChange

GERPScore

AminoAcidChange

PredictedEffect

CutisAplasia

EarAnomaly

Absent orHypoplasticNipplesand/orBreast

Family J

I-1 NA Brazilian male 2 c.92C>A 5.68 p.Pro31His missense þ � þ

II-1 NA Brazilian male 2 c.92C>A 5.68 p.Pro31His missense þ þ þ

This table depicts mutation information and associated clinical findings for individuals with SEN syndrome. Plus signs (þ) indicate the presence of a finding, andminus signs (–) indicate the absence of a finding. GERP scores provide an estimate of conservation across species at a nucleotide site; a more positive score is asso-ciated with deleteriousness. An expanded phenotype table is provided in Table S1. The following abbreviations are used: GERP, Genomic Evolutionary RateProfiling; ND, no data; NA, not applicable; and NT, not tested.

transcriptional repression even though they do not disrupt

dimerization. It remains to be determined whether substi-

tutions of amino acids not directly contributing to the

functional integrity of the BTB also cause SEN syndrome

by disrupting transcriptional repression.

One protein family with which KCTD1 interacts is the

AP-2a family of transcription factors. Specifically, KCTD1

interacts with TFAP2A, TFAP2B, and TFAP2C via its BTB

domain and acts as a strong repressor of TFAP2A transcrip-

tional activity.15 This is noteworthy because mutations in

TFAP2A cause branchiooculofacial syndrome (BOFS [MIM

113620]), one of the features of which is branchial cutis

aplasia.18 This observation suggests that the cutis aplasia

observed in SEN syndrome might result from altered regu-

lation of TFAP2A. Thus, the identified mutations within

the region encoding the BTB domain of KCTD1 in SEN

syndrome might affect its inhibitory activity on AP-2a

The Am

transactivation during embryogenesis and result in devel-

opmental defects in skin formation. It is likely that the

additional ectodermal abnormalities affecting the ears

and nipples in SEN syndrome are a consequence of altered

repressor activity of the KCTD1 BTB domain on other tran-

scription factors involved in the formation of these ecto-

dermally derived anatomic structures. This is not

surprising given that proteins with a BTB domain have

been shown to have multiple roles during embryogenesis

and tissue homeostasis, including skin structure.19

In summary, we used linkage analysis and exome

sequencing to discover that missense mutations in

KCTD1 explain the cause of SEN syndrome in all ten fami-

lies that we tested. Mutations in KCTD1 were clustered in

the region that encodes a functional pocket of its BTB

domain, the perturbation of which in other BTB-contain-

ing proteins causes loss of disruption of transcriptional

Figure 3. Genomic Structure and AllelicSpectrum of KCTD1 Mutations that CauseSEN SyndromeKCTD1 is composed of five exons thatencode UTRs (orange) and protein-coding-sequence domains (blue),including a BTB domain (red). Arrows indi-cate the locations of ten different muta-tions found in ten families affected bySEN syndrome. Carrots indicate mutationsthat were confirmed to be de novo.Deduced amino acid sequences of partialKCTD1 in multiple species are shown.Locations of amino acid residues affectedby KCTD1 mutations are shaded.

erican Journal of Human Genetics 92, 621–626, April 4, 2013 625

activity. The findings reveal a function of the KCTD1 BTB

domain during ectodermal development. Our findings

also indicate that phenotypic overlap between SEN

syndrome and BOFS might be due to a shared defect in

the same biological process and suggest that similar clinical

cases for which the gene has yet to be discovered might be

due to variants in genes that have a similar role.

Supplemental Data

Supplemental Data include two tables and can be found with this

article online at http://www.cell.com/AJHG.

Acknowledgments

We thank the families for their participation and support; Tracy

Dudding-Byth for clinical assistance; Kati Buckingham and

Christa Poel for technical assistance; and Jennifer E. Below for

discussion. Our work was supported in part by grants from the

National Institutes of Health National Human Genome Research

Institute (1U54HG006493 to M.B., D.N., and J.S.;

1RC2HG005608 to M.B., D.N., and J.S.; and 5RO1HG004316 to

H.T.), the Life Sciences Discovery Fund (2065508 and 0905001),

and the Washington Research Foundation.

Received: January 30, 2013

Revised: February 28, 2013

Accepted: March 6, 2013

Published: March 28, 2013

Web Resources

The URLs for data presented herein are as follows:

FASTX-Toolkit, http://hannonlab.cshl.edu/fastx_toolkit/

GATK, http://www.broadinstitute.org/gatk/

Human Genome Variation Society, http://www.hgvs.org/

mutnomen/

Illumina HumanCytoSNP-12 DNA Analysis BeadChip Kit, http://

www.illumina.com/products/

humancytosnp_12_dna_analysis_beadchip_kits.ilmn

NHLBI Exome Sequencing Project (ESP) Exome Variant Server,

http://evs.gs.washington.edu/EVS/

Online Mendelian Inheritance in Man (OMIM), http://www.

omim.org/

Picard, http://picard.sourceforge.net/

RefSeq, http://www.ncbi.nlm.nih.gov/RefSeq

SAMtools, http://samtools.sourceforge.net/

SeattleSeq Annotation 137, http://snp.gs.washington.edu/

SeattleSeqAnnotation137/

References

1. Finlay, A.Y., and Marks, R. (1978). An hereditary syndrome of

lumpy scalp, odd ears and rudimentary nipples. Br. J. Derma-

tol. 99, 423–430.

2. Al-Gazali, L., Nath, R., Iram, D., and AlMalik, H. (2007). Hypo-

tonia, developmental delay and features of scalp-ear-nipple

syndrome in an inbred Arab family. Clin. Dysmorphol. 16,

105–107.

626 The American Journal of Human Genetics 92, 621–626, April 4, 2

3. Baris, H., Tan, W.H., and Kimonis, V.E. (2005). Hypothelia,

syndactyly, and ear malformation—a variant of the scalp-

ear-nipple syndrome?: Case report and review of the literature.

Am. J. Med. Genet. A. 134A, 220–222.

4. Edwards, M.J., McDonald, D., Moore, P., and Rae, J. (1994).

Scalp-ear-nipple syndrome: additional manifestations. Am. J.

Med. Genet. 50, 247–250.

5. Naik, P., Kini, P., Chopra, D., and Gupta, Y. (2012). Finlay-

Marks syndrome: report of two siblings and review of litera-

ture. Am. J. Med. Genet. A. 158A, 1696–1701.

6. Paik, Y.S., and Chang, C.W. (2010). Stahl ear deformity asso-

ciated with Finlay-Marks syndrome. Ear Nose Throat J. 89,

256–257.

7. Picard, C., Couderc, S., Skojaei, T., Salomon, R., de Lonlay, P.,

Le Merrer, M., Munnich, A., Lyonnet, S., and Amiel, J.

(1999). Scalp-ear-nipple (Finlay-Marks) syndrome: a familial

case with renal involvement. Clin. Genet. 56, 170–172.

8. Plessis, G., Le Treust, M., and Le Merrer, M. (1997). Scalp

defect, absence of nipples, ear anomalies, renal hypoplasia:

another case of Finlay-Marks syndrome. Clin. Genet. 52,

231–234.

9. Sobreira, N.L., Brunoni, D., Cernach, M.C., and Perez, A.B.

(2006). Finlay-Marks (SEN) syndrome: a sporadic case and

the delineation of the syndrome. Am. J. Med. Genet. A. 140,

300–302.

10. Taniai, H., Chen, H., and Ursin, S. (2004). Finlay-Marks

syndrome: another sporadic case and additional manifesta-

tions. Pediatr. Int. 46, 353–355.

11. Aase, J.M., and Wilroy, S.R. (1988). The Finlay-Marks (SEN)

syndrome: Report of a new case and review of the literature.

Proceedings of the Greenwood Genetics Center 7, 177–178.

12. LeMerrer, M., Renier, D., and Briard, M.L. (1991). Scalp defect,

nipples absence and ears abnormalities: an other case of Finlay

syndrome. Genet. Couns. 2, 233–236.

13. Li, H., and Durbin, R. (2009). Fast and accurate short read

alignment with Burrows-Wheeler transform. Bioinformatics

25, 1754–1760.

14. Ding, X.F., Luo, C., Ren, K.Q., Zhang, J., Zhou, J.L., Hu, X., Liu,

R.S., Wang, Y., Gao, X., and Zhang, J. (2008). Characterization

and expression of a human KCTD1 gene containing the BTB

domain, which mediates transcriptional repression and ho-

momeric interactions. DNA Cell Biol. 27, 257–265.

15. Ding, X., Luo, C., Zhou, J., Zhong, Y., Hu, X., Zhou, F., Ren, K.,

Gan, L., He, A., Zhu, J., et al. (2009). The interaction of KCTD1

with transcription factor AP-2alpha inhibits its transactiva-

tion. J. Cell. Biochem. 106, 285–295.

16. Zollman, S., Godt, D., Prive, G.G., Couderc, J.L., and Laski, F.A.

(1994). The BTB domain, found primarily in zinc finger

proteins, defines an evolutionarily conserved family that

includes several developmentally regulated genes in

Drosophila. Proc. Natl. Acad. Sci. USA 91, 10717–10721.

17. Ahmad, K.F., Engel, C.K., and Prive, G.G. (1998). Crystal struc-

ture of the BTB domain from PLZF. Proc. Natl. Acad. Sci. USA

95, 12123–12128.

18. Milunsky, J.M., Maher, T.A., Zhao, G., Roberts, A.E., Stalker,

H.J., Zori, R.T., Burch, M.N., Clemens, M., Mulliken, J.B.,

Smith, R., and Lin, A.E. (2008). TFAP2A mutations result in

branchio-oculo-facial syndrome. Am. J. Hum. Genet. 82,

1171–1177.

19. Gebhardt, A., Kosan, C., Herkert, B., Moroy, T., Lutz,W., Eilers,

M., and Elsasser, H.P. (2007). Miz1 is required for hair follicle

structure and hair morphogenesis. J. Cell Sci. 120, 2586–2593.

013